Compounds derived from 6-azaindoles as ligands of the benzodiazepine receptor and medicaments containing them

ABSTRACT

PCT No. PCT/FR92/00480 Sec. 371 Date Nov. 29, 1993 Sec. 102(e) Date Nov. 29, 1993 PCT Filed May 29, 1992 PCT Pub. No. WO/9221680 PCT Pub. Date Dec. 10, 1992.New 6-azaindole derivatives as ligands of the benzodiazepine receptor, pharmaceutical compositions containing these compounds, processes for producing these compounds and also compounds which are useful in particular as intermediates in the processes of preparation.

This application is a 371 of PCT/FR92/00480, filed 29 May 1992.

The invention relates to new 6-azaindole derivatives as ligands of thebenzodiazepinee receptor, to the pharmaceutical compositions containingthese compounds, to the processes for producing said compounds and alsoto the compounds which are useful in particular as intermediates in theprocesses of preparation.

1,4-Benzodiazepines (for example Valium) constitute a class ofwidely-prescribed medicaments due to their anxiolytic, anticonvulsant,sedative/hypnotic and muscle relaxant activities. The mechanism ofaction of the benzodiazepines remained unrecognized for a long timeuntil the discovery of specific binding sites (or "receptors") for thesemolecules on the neuronal membranes of the central nervous system. Thephysiological importance of these receptors was demonstrated by theexistence of good correlation between, on the one hand, the value of theaffinity of the various benzodiazepines for the receptor (measured bydisplacement of a radioactive benzodiazepine) and, on the other hand,their therapeutic effectiveness.

Likewise, it was found that certain β-carbolines behaved as agonists ofthe benzodiazepine receptor.

Thus, Abecarnil, developed by Schering as an anxiolytic, ##STR1## is inthe course of clinical trials. Other related β-carboniles such as ZK93423 and ZK 91296 also possess properties analogous to those ofdiazepam in vivo (anxiolytic, anticonvulsant, and the like).

While searching for an endogenous ligand of the benzodiazepine receptor,Braestrup et al. (Proc. Natl. Acad. Sci., USA, 77, 2288-2292, 1980)discovered a molecule, the ethyl ester of β-carboline-3-carboxylic acid(β-CCE), extracted from human urine, which binds with very good affinityto the central receptors of benzodiazepines (IC₅₀ =4 nM, in vitro, ratbrain). On the other hand, β-CCE has pharmacological effects in vivowhich are opposite to those of the benzodiazepines. Thus, β-CCE is aproconvulsant in mice, facilitating the convulsions caused by otheragents such as pentylenetetrazole. ##STR2##

The term "inverse agonist" is now used to denote these ligands of thebenzodiazepine receptor which have activities completely or partiallyopposed to those of the benzodiazepines.

The therapeutic advantage of the β-carbolines lies at several levels.Thus, the team which is the author of the present invention was thefirst to demonstrate that such molecules (for example β-CCM below),##STR3## inverse agonists of the benzodiazepine receptor, have apositive effect on learning and memory (Venault et al., Nature, 321,864-866, 1986). Although β-CCM could not be tested in man for itsmemory-enhancing effects due to its highly convulsant activity, otheranalogues such as ZK 93426 or Flumazenil, which are antagonists of thebenzodiazepine receptor, were tested in man where their memory-enhancingproperties were revealed (Duka et al., Psychopharmacology, 93, 42-427,1987 and Lal et al., Pharmacol, Biochem. Behav., 35, 747-750, 1990).##STR4##

Thus, it would seem that antagonists or partial inverse agonists of thebenzodiazepine receptor are useful in the treatment of certain cognitiveproblems such as Alzheimer's disease.

Moreover, 6-azaindole derivatives are known, some of which have beentested for their suitability on the central nervous system.

Thus, the authors of the present invention have described the synthesisof 2,5-dicarbethoxy-6-azaindole by the Frydman method (Dodd et al.,Heterocycles, 28, 1101-1113, 1989). This molecule only has a very weakaffinity for the benzodiazepine receptor in vitro (IC₅₀ =84,000 nM).

Other compounds have been described by some of the authors of theinvention in collaboration with other researchers (Dodd et al., J. Med.Chem., 32, 1272-1276, 1989 and Dellouve-Courillon et al., Tetrahedron,46, 3245-3266, 1990).

However, no indication regarding their properties with respect tobenzodiazepine receptors was reported.

For example, the compound of formula: ##STR5## was described in theabovementioned publication by Dellouve-Courillon.

Likewise, the 6-azaindoles (mono-, di- and trisubstituted) mentionedbelow have been described in the literature (Frydman et al., J. Am.Chem. Soc., 87, 3530-3531, 1965; Frydman et al., J. Org. Chem., 33,3762-3766, 1968; Fischer et al., J. Med. Chem., 15., 1168-1171, 1972;Prokopov et al., Chem. Het. Compounds, 4, 406-410, 1978; Clark et al.,J. Chem. Soc., (C), 498-501, 1970; Fischer et al., J. Het. Chem., 6,775-776, 1969; Yakhontov et al., Russian Chem. Rev., 49, 428-444, 1980).##STR6##

    R=H, OCH.sub.3, OCH.sub.2 C.sub.6 H.sub.5

    R'=H, CH.sub.2 CH.sub.2 CO.sub.2 H, CH.sub.2 N(CH.sub.3).sub.2, CHO, CH=NOH CN, CH.sub.3, CH.sub.2 NH.sub.2, NO.sub.2, Br

    R"=H, CO.sub.2 H, CO.sub.2 C.sub.2 H.sub.5, CONH.sub.2, CN, C.sub.6 H.sub.5, CHO, CH.sub.2 OH

None of these molecules is known for interacting with the benzodiazapinreceptor.

Finally, Patent DE-A-3,525,928 describes the synthesis of5,6,7,8-tetrahydro-β-carboline derivatives.

Consequently, one of the aims of the present invention is to propose newcompounds having an affinity with the benzodiazapin receptor whilehaving an at least partial inverse agonist effect.

Another aim of the present invention is to propose new therapeuticcompositions which are useful in particular in the treatment of nervousdisorders.

Another aim of the present invention is to propose new therapeuticcompositions having a positive effect on learning and memory and whichcan be used for the treatment of cognitive problems such as, forexample, in Alzheimer's disease.

The invention relates, in the first place, to the 6-azaindole offormula: ##STR7## in which: R₁ represents the hydrogen atom or a groupR₅ --O--CH₂ -- in which R₅ corresponds to an alkyl radical optionallysubstituted by one or a number of alkoxy, alkylthio, alkylcarbonyl,amino, nitro or cyano groups or a to a group of formula Ar--Z,

in which:

Z is a saturated or unsaturated divalent radical having from 1 to 5atoms preferably chosen from --CH₂ --, --CH₂ CH₂ --, --CH═CH-- or--CH═CH--CH₂ --,

Ar is an optionally substituted phenyl or heteroaryl radical containing5 to 6 atoms in the ring including 1 to 3 heteroatoms,

R₂ is an alkoxy, cycloalkoxy, aryloxy, aralkoxy, N-alkyl-substitutedamino, N-cycloalkyl-substituted amino or N-phenyl-substituted aminoradical, it being possible for the aromatic parts to be optionallysubstituted,

R₃, R₄ independently represent the hydrogen atom or an alkyl radical,

with the exception of the compound where R₁, R₃ and R₄ are the hydrogenatom and R₂ is the N-(2-carboxyphenyl)amino radical, and thepharmacologically acceptable salts of these compounds.

In the present description, the alkyl or alkoxy radicals preferably havefrom 1 to 6 carbon atoms and can be linear or branched (preferablylinear). The aryl or aryloxy radicals preferably have 6 to 10 carbonatoms and the aralkyl or aralkoxy radicals from 7 to 11 carbon atoms.

Mention may be made, among the heteroaryl radicals, of the 1- or 2- or3-pyridyl, 1- or 2- or 3-pyrrolyl, 2- or 3-thienyl, 2- or 3-furyl, or 1-or 2- or 3- or 4-imidazolyl radicals or the various pyrimydinylradicals.

Mention may be made, among the substituents of the phenyl or heteroarylcompounds, of weakly hindered donor radicals such as halogen atoms ornitro, cyano, optionally halogenated alkoxy, optionally halogenated C₁-C₃ alkyl, linear in the case of C₃, CF₃ in particular, or SO₃ Hradicals.

Moreover, certain compounds have one or a number of asymmetric centres.They can therefore exist in one or a number of optically active forms.In this case, the invention comprises said optically active forms ofthese compounds.

Mention may be made, among these salts, of: chlorides, hydrochlorides,tartrates or fumarates.

According to a preferred variant, the R₁ group corresponds to the groupof formula ##STR8## in which: X is a weakly hindered electron-donatingradical,

n is a positive integer or zero, less than 6, it being possible for theX groups to be identical or different when n is greater than 1.

Mention may be made, among the electron-donating X radicals, preferablyof halogen atoms or nitro, cyano, optionally halogenated alkoxy,optionally halogenated C₁ -C₃ alkyl, linear in the case of C₃, inparticular CF₃, or SO₃ H radicals and preferably n=0, 1, 2 or 3.

According to a preferred variant, the R₁ group corresponds to the groupof formula III: ##STR9## or R₁ is a methyl group substituted by analkoxy radical and COR₂ is preferably an ester functional group.

According to another preferred variant, R₁ is a hydrogen atom and COR₂is preferably an amide functional group, R₂ advantageously being anN-aryl amide, in particular N-phenylamide, optionally substituted by oneor a number of radicals chosen from carboxyl, sulfonate or acidphosphonate radicals.

It has in fact been found, in an entirely unexpected way, that certainamides according to the invention showed affinities with respect to ratcortex which were greater than those of the esters.

Furthermore, in the β-CCM series, for the first time molecules have beenprovided containing an amide group which have good properties withrespect to the desired goal. These molecules additionally have a numberof advantages:

a better hydrolytic stability;

a new point of interaction with the benzodiazepine receptor.

The invention also relates to the processes for the preparation of thecompounds according to the invention.

In the description which follows, except when otherwise indicated, theR₁ to R₅ substituents have the same meaning as above.

a) process for the preparation of the compounds of formula I in whichR₂, R₃ and R₄ have one of the meanings indicated above and R₁corresponds to the R₅ --OCH₂ group.

This process consists in reacting a compound of formula: ##STR10## inwhich R₆ and R₇ are independently the hydrogen atom or a C₁ -C₄ alkylradical,

R₈ is (C₁ -C₄)alkyl, (C₃ -C₆)cycloalkyl, (C₆ -C₁₀)aryl or (C₇-C₁₁)aralkyl, the aromatic rings optionally being substituted as for R₂,

in the presence of the sodium salt of a carboxylic acid R₉ COOH (R₉ =C₁-C₄ alkyl), in particular acetic acid, in the corresponding anhydride atreflux in order to obtain the compound of formula: ##STR11## and in thenreacting the latter compound with an alcohol R₅ OH, in the presence of aweak acid (for example paratoluenesulfonic acid) and a polar aproticsolvent such as acetonitrile, which leads to the desired compound offormula I. The ester function group at the 5 position is converted to anamide functional group in a known way. It is also possible, in a firststep, to convert the COOR₈ ester group to an amide group (compound Va)and then to react the R₅ OH group.

The compound of formula IV is prepared by reacting a compound offormula: ##STR12## with a halide of a ##STR13## cation in a known way.

b) Process for the preparation of the compounds of formula I in which:

R₂, R₃ and R₄ have one of the meanings indicated above and R₁corresponds to the hydrogen atom.

This process consists in converting the compound of formula: ##STR14##to an amide or ester functional group in a known way.

For example, production of the amide functional group is assuredaccording to the instructions of the abovementioned publication byDellouve-Courillon.

Thus, one of the subjects of the invention is also the compounds offormula: ##STR15## and Va which are useful in particular asintermediates in the preparation processes indicated above.

The compound of formula VII is prepared by esterification of thecorresponding acid VI which is itself prepared by oxidation of thealdehyde VIII. The latter is obtained in a known way, for exampleaccording to the reaction scheme described in the abovementionedpublication by Dellouve-Courillon et al.

The invention also relates to the medicaments consisting of one of thecompounds according to the invention and the compound of formula I inwhich R₁, R₃ and R₄ are the hydrogen atom and R₂ theN-(2-carboxyphenyl)amino radical such as have just been described aboveand to the pharmaceutical compositions containing at least one of thesemedicaments and an acceptable vehicle. These medicaments andcompositions are useful for the medical or veterinary treatment ofcertain disorders related to the functioning of the nervous system.

These medicaments and compositions are particularly intended to be usedin combination with benzodiazapins in order to compensate for theharmful effects due to the use of the latter. These compounds themselvesalso promote learning and the retention of information in man.

These medicaments and compositions can thus be advantageously intendedto participate in an effective therapy against degenerative diseases ofthe nervous system, in particular Alzheimer-type dementias.

The pharmaceutical compositions are in particular formulated to beingested orally or to be injected. Nevertheless, other presentations canalso be envisaged within the context of the present invention.

The dosage will depend partly on the illness to be treated and on itsseriousness and also on the type of the individual (weight, age).

A dosage ranging from 0.1 mg/kg to 20 mg/kg could advantageously beenvisaged.

The examples below illustrate the invention:

EXAMPLE 1

Preparation of Methyl 3-Benzyloxymethyl-6-Azaindole-5-Carboxylate##STR16##

A--Preparation of Methyl3-(N,N-Dimethylaminomethyl)-6-Azaindole-5-Carboxylate ##STR17##

234.4 (2.50 mmol) of N,N-dimethylmethyleneiminium chloride are added to296.0 mg (1.68 mmol) of ester (R₁ =R₃ =R₄ H, R₂ OCH₃) in 30 ml of dryacetonitrile and the mixture is maintained at reflux overnight. Theprogress of the reaction is monitored by TLC (80/20chloroform/methanol). The reaction mixture is then cooled andconcentrated under vacuum. It is then basified with a saturated sodiumbicarbonate solution and then extraction is carried out withdichloromethane. The organic phases are combined, washed with water andthen a sodium chloride solution [lacuna] is dried over magnesiumsulfate. The solvent is evaporated under reduced pressure, leaving aresidue which is crystallized from a mixture of dichloromethane andacetonitrile to lead to 171.2 mg (43%) of azagramine.

M.p. (dichloromethane/acetonitrile)=217° C.

B--Preparation of MethylN-Acetyl-3-Acetoxymethyl-6-Azaindole-5-Carboxylate ##STR18##

51.2 mg (0.22 mmol) of the above azagramine and 44.6 mg (0.54 mmol) ofanhydrous sodium acetate are dissolved in 1 ml of distilled aceticanhydride and the mixture is maintained at reflux for 1 hour. Theprogress of the reaction is monitored by TLC (80/20 chloroform methanol)and, when it is complete, the reaction mixture is cooled. It is thenneutralized with a saturated sodium bicarbonate solution and extractedwith dichloromethane. The organic phases are combined, washed with waterand dried over magnesium sulfate. The solvent is evaporated underreduced pressure, leaving a residue which is chromatographed on apreparative plate (97.5/2.5 dichloromethane/ethanol) to lead to thediacetylated derivative which is crystallized from a mixture ofchloroform, ethyl acetate and nHexane (50.4 mg: 79%).

M.p. (chloroform/ethyl acetate/n-Hexane)=170°-172° C.

C--Preparation of Methyl 3-Benzyloxymethyl-6-Azaindole-6-Carboxylate##STR19##

9.6 mg (0.03 mmol) of the above diacetate, 9.8 mg (0.05 mmol) ofparatoluenesulfonic acid monohydrate and 4.1 μl (0.04 mmol) of benzylalcohol in 3 ml of dry acetonitrile are maintained at reflux for 48hours. The disappearance of the starting material is monitored by TLC(90/10 dichloromethane/ethanol). The solution is cooled, basified with asaturated sodium bicarbonate solution and extracted withdichloromethane. The organic phases are combined, washed with water andthen with a saturated sodium chloride solution, dried over magnesiumsulfate and then evaporated under vacuum. The residue is chromatographedon a preparative plate (90/10 dichloromethane/ethanol) and thencrystallized from a mixture of chloroform and n-Hexane, leading to 5.4mg (55%) of the 3-benzyloxymethyl derivative.

M.p. (chloroform/n-Hexane)=191° C.

By employing the same synthetic process, but with suitable startingmaterials, the following compounds were obtained:

    ______________________________________                                         ##STR20##                                                                    Examples    R.sub.10     °M.p. [sic]                                   ______________________________________                                        2           CH.sub.3     156                                                  3           2F-PhCH.sub.2                                                                              193                                                  4           3F-PhCH.sub.2                                                                              171                                                  5           4F-PhCH.sub.2                                                                              201                                                  6           2NO.sub.2 -PhCH.sub.2                                                                      266                                                  7           3NO.sub.2 -PhCH.sub.2                                                                      260                                                  8           4NO.sub.2 -PhCH.sub.2                                                                      238                                                  9           3MeO-PhCH.sub.2                                                                            188                                                  10          PhCH.sub.2 CH.sub.2                                                                        233                                                  11          PhCHCHCH.sub.2                                                                             228                                                  ______________________________________                                    

EXAMPLE 12

Preparation of 5-Phenylamido-6-Azaindole-2'-Carboxylic Acid ##STR21##

The acid (R₁ =R₃ =R₄ =H, R₂ =OH) (31.2 mg, 0.19 mmol) is dissolved in 3ml of dry tetrahydrofuran to which 120 μl of distilled triethylamine areadded. The reaction mixture is cooled to 0° C. and 50 μl (0.64 mmol) ofdistilled ethyl chloroformate are added dropwise. The solution isallowed to return to room temperature and then the temperature isbrought to 40° C. The progress of the reaction is monitored by TLC(dichloromethane) and, when it is complete, the mixture is cooled andevaporated dryness. 5 ml of dry tetrahydrofuran and 26 μl (0.20 mmol) ofmethyl anthranilate are added thereto and the mixture is brought toreflux. The progress of the reaction is monitored by TLC(dichloromethane) and, when it is complete, the mixture is cooled andevaporated to dryness. The residue is taken up in dichloromethane andbasified with a saturated sodium bicarbonate solution. The aqueous phaseis extracted with dichloromethane. The organic phases are combined andwashed with water, then a saturated sodium chloride solution and driedover magnesium sulfate. The solvent is evaporated under vacuum, leavinga residue which is chromatographed on a preparative plate(dichloromethane). Compound 16 is crystallized from a mixture ofdichloromethane and n-Hexane (31.2 mg, 44%).

M.p. (dichloromethane/n-Hexane)=198°-199° C.

According to the same method, but with the corresponding aromaticamines, the following compounds were obtained:

    ______________________________________                                         ##STR22##                                                                    Examples      R        °M.p.                                           ______________________________________                                        13            H        225                                                    14            3-COOH   310 (decomp)                                           15            4-COOH   305 (decomp)                                           ______________________________________                                    

Compound 16 (31 mg, 0.08 mmol) is dissolved in 5 ml of 10% aqueousethanol to which 420 μl of 1N sodium hydroxide solution are added andthe mixture is brought to reflux. After one hour, the reaction mixtureis complete (95/5 dichloromethane/ethanol). The reaction mixture iscooled and the ethanol is evaporated. A few drops of water are added andthe acid 12 is precipitated by controlled addition of acetic acid. Afterleaving overnight at 4° C., the precipitate is filtered, washed withwater and dried to give 21.5 mg (91%) of acid 12.

M.p. (H₂ O)=286°-297° C.

BIOLOGICAL PROPERTIES

A--In Vitro Tests on Cortex Membrane

The compounds of Examples 1 to 14 were tested on rat cortex membrane inorder to determine their affinity for the benzodiazepine receptor.

The measurements are summarized in the table below.

    ______________________________________                                               Examples                                                                             IC.sub.50 (nM)                                                  ______________________________________                                               1       750                                                                   2      1500                                                                   3       65                                                                    4       100                                                                   5       75                                                                    6      1200                                                                   7      1300                                                                   8       300                                                                   9      10000                                                                  10       8                                                                    11      150                                                                   12      300                                                                   13     7000                                                                   14     5500                                                                   15     2300                                                            ______________________________________                                    

B--Pharmacological Property of the Compound of Example 1 Determinationof the Pharmacological Profile

This study consists of an electrophysiological test on Xenopus oocyte.The cells of chicken optical lobes fortuitously have a good response toGABA. The total RNAs are extracted therefrom and passed through anoligo(dT) affinity column, thus making it possible to separate the crudemessenger RNAs therefrom, because the latter have a poly(A) end tailwhich will combine by complementarity with the oligo(dT) residues of thecolumn. These messenger RNAs will then be injected into a Xenopusoocyte, which is only a one and only cell. These oocytes will then beincubated and, in two days, the messenger RNAs will be expressed andwill thus, by virtue of the cell machinery of the oocyte, have producedGABA receptor/benzodiazepine receptor/chloride channel complexes. Theselarge protein entities will then migrate in the cell and will reach themembrane, thus making it possible for this receptor and thetransmembrane ion channel which is combined with it to take its place.

The oocyte is then placed in a 10⁻⁵ M GABA bath in Ringer solution andtwo microelectrodes A and B are introduced therein, a thirdmicroelectrode being placed outside the cell to act as reference.Microelectrode A will be used to measure the potential difference (PD)between the interior and the exterior of the oocyte. A PD of 60 mV isimposed on the oocyte and the microelectrode B will be used to maintainthis desired PD.

By perfusing an agonist such as diazepam, the latter and the GABApresent in the medium will exert an allosteric effect at the level ofthe receptor with, as corollary, opening of the ion channel. There willtherefore be entry of chloride into the oocyte and the PD will greatlyincrease. On the other hand, an inverse agonist such as β-CCM will causea reduction in the binding of the GABA to the receptor with, asconsequence, a reduction in the time of opening of the chloride channeland a lower PD.

An antagonist will occupy the binding site of the benzodiazepinereceptor but will have no effect on the binding of the GABA. The openingof the chloride channel will therefore not be disturbed and the PD willnot vary.

Compound 1 was perfused in the medium bathing the oocyte at aconcentration of 10⁻⁶ M, causing, with respect to the great increase ofthe diazepam and the significant reduction of the β-CCM, a slightreduction of the PD. Molecule 1 is therefore a partial inverse agonist,whereas ZK 91296 is a partial agonist.

IN VIVO TESTS

Compound 1 was tested first for its convulsant properties. The test wascarried out on 14 mice (5 males and 9 females) aged two months belongingto the ABP/Le strain. This particular strain is very sensitive toconvulsions induced by β-carbolines. Compound 1 was administeredintraperitoneally at a dose of 20 mg/kg and observation took place after30 minutes. None of the mice showed the least convulsion. The compoundis therefore not convulsant.

Compound 1 was then tested on learning. This test, passive avoidancewith learning in a single test, was carried out on 30 female Swiss miceaged two months. Compound 1 was administered to 15 mice at a dose of 20mg/kg, the other 15 receiving an injection of physiological serum.

The equipment consists of a white box connected to a black box by adoor. The white box is lit by a 100 W lamp placed at a distance of 25 cmand the black box, into which the mouse will spontaneously go becauseshe feels safe in the darkness, contains an electrified metal floor. Theboxes are coated with the smell of mice by an animal placed insidebefore each of the two series of 15 mice.

The test takes place in two sessions: the first is the learning and thesecond, which takes place 24 hours afterwards, is the avoidance testproper.

Ten minutes before learning, the marked mice receive an intraperitonealinjection of physiological serum or of Compound 1. The injection iscarried out with the test in order to verify if the molecule tested actson the memory at the level of the acquisition phenomenon. If the phaseof retention of the information had been studied, the injection wouldhave taken place after the learning test. The mice were then placed oneby one in the illuminated white box and the arrival time in the blackbox is recorded. This time is on average 24 seconds and the criterionused is that the four paws of the mouse are inside the black box. Atthis precise moment, an electrical shock of 75 μA of direct current istriggered for two seconds.

After 24 hours, the avoidance test takes place: the mouse is placed inthe white box and whether or not the mouse enters the black box in threeminutes is recorded without any electrical shock being caused. If themouse enters the black box in less than three minutes, the moleculetested has not improved the acquisition of the information "blackbox=electric shock" but if the time recorded is greater than threeminutes, the molecule is assumed to have acted.

    ______________________________________                                                      <3 mm  >3 mm                                                    ______________________________________                                        Treated         4        11                                                   Untreated       8         7                                                   ______________________________________                                    

It is recorded that in the animals treated with the molecule, a majority(75%) of them learnt to avoid the electric shock. The memory-enhancingeffect of the compound during the passive avoidance test with learningin a single test has therefore been revealed.

We claim:
 1. A 6-azaindole compound of the formula: ##STR23## in which:R₁ represents the hydrogen atom or a group R₅ --O--CH₂ -- in which R₅corresponds to an alkyl radical or to a group of formula Ar--Z,in which:Z is a divalent alkyl or alkenyl radical having from 1 to 5 atoms, Ar isan optionally substituted phenyl radical, R₂ is an alkoxy, cycloalkoxy,aryloxy, aralkoxy, N-alkyl-substituted amino, N-cycloalkyl-substitutedamino or N-phenyl-substituted amino radical, wherein the aromatic ringsare optionally substituted, R₃ and R₄ independently represent anhydrogen atom or an alkyl radical,with the exception of the compoundwhere R₁, R₃ and R₄ are an hydrogen atom and R₂ is theN-(2-carboxyphenyl)amino radical, or its pharmacologically acceptablesalt.
 2. A 6-Azaindole compound according to claim 1, characterized inthat Ar--Z corresponds to a group: ##STR24## in which: X is a weaklyhindered electron-donating radical,n is zero or a positive integer lessthan 6, wherein X can be identical or different when n is greaterthan
 1. 3. A 6-Azaindole compound according to claim 2, characterized inthat X is selected from halogen, nitro, cyano, optionally halogenatedalkoxy, optionally halogenated C₁ -C₃ alkyl, or linear propyl.
 4. A6-Azaindole compound according to claims 2 to 3, characterized in that nis 0, 1, 2 or
 3. 5. A 6-Azaindole compound according to claim 1,characterized in that R₁ corresponds to the group of formula III:##STR25## in which: X is a weakly hindered electron-donating radical,nis zero or a positive integer less than 6, wherein X can be identical ordifferent when n is greater than 1, or R₁ is a methyl group substitutedby an alkoxy radical.
 6. A 6-Azaindole compound according to claim 5,characterized in that R₂ is C₁ -C₆ alkoxy group.
 7. A 6-Azaindolecompound according to claim 1, characterized in that R₁ is a hydrogenatom.
 8. A 6-Azaindole compound according to claim 7, characterized inthat R₂ is N-alkyl-substituted amino, N-cycloalkyl-substituted amino orN-phenyl-substituted amino.
 9. A 6-Azaindole compound according to claim8, characterized in that R₂ is N-phenylamino optionally substituted byone or more radicals selected from the group consisting of carboxy,sulfonate and acid phosphonate radicals.
 10. A medicament consisting ofa compound according to claim 1 wherein R₁, R₃ and R₄ are hydrogen andR₂ is N-(2-carboxyphenyl)amino.
 11. A pharmaceutical compositioncontaining at least one medicament according to claim 10 and anacceptable vehicle.
 12. A 6-Azaindole compound according to claim 1,characterized in that Z is selected from --CH₂, --CH₂ --CH₂ --,--CH═CH-- or --CH═CH--CH₂.
 13. A 6-Azaindole compound according to claim3, characterized in that X is selected from CF₃ or SO₃ H.
 14. A6-Azaindole compound according to claim 9, characterized in that R₂ isN-phenylamino which is optionally substituted by one or more radicalschosen from carboxy, sulfonate or acid phosphonate radicals.